The research program of the Chronicity of Viral Infections [CVI] Emerging Team is currently divided in two research axes:

- Macrophages are durable hosts for viral pathogens via infection of common myeloid progenitors  

Chronic inflammation is commonly observed in HIV-infected patients despite antiretroviral treatment and in individuals with post-acute sequelae of COVID-19. We are investigating: i) whether macrophages precursors (common myeloid progenitors) are primed early at the bone marrow stage by a first inflammatory stimulus (e.g. viral primo-infection), displaying thereafter an enhanced inflammatory response upon a second stimulus (e.g. re-infection or superinfection) once they are terminally differentiated into tissue-like macrophages; and ii) whether this trained response is directly implicated in persistent viral replication in tissular macrophages, sustaining infection and chronic inflammation deleterious for the homeostasis.

- Megakaryocytes targeted by viruses participate in infectious disease progression

Megakaryocytes, precursor of platelets, are gaining momentum in immunology field as inflammatory/immune system actors – a poorly understood but exciting topic in immunology. We will investigate the detrimental consequences of megakaryocyte infection for the immune system and the cellular/molecular mechanisms controlling viral persistent in this myeloid cell. We aim at deciphering the megakaryocyte factors expressed upon viral infections that will be inherited by their daughter platelets and that thereafter will immunomodulate immune cells upon platelet-cell contact. Virus-induced, platelet druggable targets will be functionally assessed by blockage/inhibition using antibodies and CRISPR/Cas9 strategies, in in vitro and in vivo models, opening avenues for novel therapeutical strategies.

Recent discoveries:

Despite undetectable plasma viral load as a result of current antiretroviral therapy, HIV-infected individuals with poor immune reconstitution harbor infectious HIV within platelets. The presence of HIV in platelets is strongly correlated with poor immune reconstitution despite therapy. Megakaryocytes, in which proviral DNA and viral RNA were detected in these individuals, appear to be the likely origin of HIV-containing platelets. To investigate the mechanisms by which megakaryocytes support HIV-1 infection, we established in vitro models of viral infection in megakaryocytes derived from human CD34+ hematopoietic stem cells and in megakaryocyte cell lines. The integration of HIV proviral DNA into the megakaryocyte cell genome, self-limited viral production and HIV accumulation in virus-containing compartments - all features illustrating viral infection and HIV persistence within myeloid cells - have been established.

The team is investigating the mechanisms of virus-induced defusal of megakaryocytes’ antiviral factors, in particular the hijacking of the immune response mediated by interferon-induced transmembrane protein 3 (IFITM3). IFITM3 is an antiviral factor constitutively expressed by megakaryocytes, whose expression is enhanced by interferon alpha. IFITM3 expression was inhibited by HIV infection, without affecting the maturation of infected megakaryocytes. To investigate the involvement of IFITM3 in HIV infection, IFTIM3 gene expression was knocked-down using gene silencing techniques. As effect of IFTIM3 silencing, HIV infection is enhanced in megakaryocytes. Overall, these results suggest that HIV counteract the intrinsic antiviral response conferred on megakaryocytes by IFITM3. Megakaryocytes and platelets are largely neglected hideouts of HIV that deserve to be studied for the development of improved antiretroviral therapies and, above all, to achieve complete eradication of HIV infection.